A comparison of the effects of forskolin and nitroprusside on cyclic nucleotides and relaxation in the rat aorta.

Forskolin (FOR), a diterpene activator of adenylate cyclase, produced time- and dose-dependent increases in cAMP, cAMP-dependent protein kinase activation and relaxation in the contracted rat aorta but had no effect on cGMP levels. Nitroprusside (NP) increased cGMP levels and relaxation but had no effect on cAMP levels. cAMP-dependent protein kinase activation was seen with higher concentrations of NP. Major differences were observed in the modes of action of the two compounds: (1) the time course of relaxation to FOR was slower than that to NP (15 min vs. 3 min) even though the cAMP-dependent protein kinase activity ratio was maximally elevated at 3 min after the addition of FOR; (2) FOR and dibutyryl cAMP prevented contraction to both norepinephrine (NE) and KCl whereas NP and 8-bromo-guanosine 3',5'-monophosphate (8-Br-cGMP) were more effective in preventing contraction to NE than to KCl. In addition, the analog of cGMP was more effective in preventing contraction to KCl at lower concentrations of external Ca2+ while the analog of cAMP prevented contraction to KCl at all concentrations of Ca2+ equally. Nevertheless, some similarities in the actions of FOR and NP were apparent in that both agents relaxed the NE-contracted aorta more effectively than the KCl-contracted aorta, and both agents relaxed aorta contracted with lower doses of NE more effectively than that contracted with high doses of NE. These results suggest that although some similarities in the relaxing action of rat aorta by FOR and NP exist, major differences are apparent which suggests that the two compounds exert these effects through unique biochemical mechanisms.